PMID- 33101846 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240330 IS - 2198-3844 (Print) IS - 2198-3844 (Electronic) IS - 2198-3844 (Linking) VI - 7 IP - 20 DP - 2020 Oct TI - EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis. PG - 2000681 LID - 10.1002/advs.202000681 [doi] LID - 2000681 AB - Forkhead-Box Class O 4 (FOXO4) is involved in critical biological functions, but its response to EGF-PKB/Akt signal regulation is not well characterized. Here, it is reported that FOXO4 levels are downregulated in response to EGF treatment, with concurrent elevation of COP9 Signalosome subunit 6 (CSN6) and E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1) levels. Mechanistic studies show that CSN6 binds and regulates FOXO4 stability through enhancing the E3 ligase activity of COP1, and that COP1 directly interacts with FOXO4 through a VP motif on FOXO4 and accelerates the ubiquitin-mediated degradation of FOXO4. Metabolomic studies demonstrate that CSN6 expression leads to serine and glycine production. It is shown that FOXO4 directly binds and suppresses the promoters of serine-glycine-one-carbon (SGOC) pathway genes, thereby diminishing SGOC metabolism. Evidence shows that CSN6 can regulate FOXO4-mediated SGOC gene expression. Thus, these data suggest a link of CSN6-FOXO4 axis and ser/gly metabolism. Further, it is shown that CSN6-COP1-FOXO4 axis is deregulated in cancer and that the protein expression levels of CSN6 and FOXO4 can serve as prognostic markers for cancers. The results illustrate a pathway regulation of FOXO4-mediated serine/glycine metabolism through the function of CSN6-COP1 axis. Insights into this pathway may be strategically designed for therapeutic intervention in cancers. CI - (c) 2020 The Authors. Published by Wiley-VCH GmbH. FAU - Choi, Hyun Ho AU - Choi HH AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. AD - Guangdong Research Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. FAU - Zou, Shaomin AU - Zou S AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. AD - Guangdong Research Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. FAU - Wu, Jian-Lin AU - Wu JL AD - State Key Laboratory of Quality Research in Chinese Medicine Macau Institute for Applied Research in Medicine and Health Macau University of Science and Technology Macao 999078 China. FAU - Wang, Huashe AU - Wang H AD - Department of Colorectal Surgery The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. FAU - Phan, Liem AU - Phan L AD - Department of Molecular and Cellular Oncology Division of Basic Science Research The University of Texas MD Anderson Cancer Center Houston TX 77030 USA. FAU - Li, Kai AU - Li K AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. AD - Guangdong Research Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. FAU - Zhang, Peng AU - Zhang P AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. AD - Guangdong Research Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. FAU - Chen, Daici AU - Chen D AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. AD - Guangdong Research Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. FAU - Liu, Qingxin AU - Liu Q AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. AD - Guangdong Research Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. FAU - Qin, Baifu AU - Qin B AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. AD - Guangdong Research Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. FAU - Nguyen, Thu Anh Thai AU - Nguyen TAT AD - Department of Biotechnology Nong Lam University Ho Chi Minh City 700000 Vietnam. FAU - Yeung, Sai-Ching J AU - Yeung SJ AD - Department of Emergency Medicine Division of Internal Medicine The University of Texas MD Anderson Cancer Center Houston TX 77030 USA. FAU - Fang, Lekun AU - Fang L AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. AD - Guangdong Research Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. AD - Department of Colorectal Surgery The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. FAU - Lee, Mong-Hong AU - Lee MH AUID- ORCID: 0000-0001-8675-8215 AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. AD - Guangdong Research Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655 China. LA - eng PT - Journal Article DEP - 20200923 PL - Germany TA - Adv Sci (Weinh) JT - Advanced science (Weinheim, Baden-Wurttemberg, Germany) JID - 101664569 PMC - PMC7578864 OTO - NOTNLM OT - COP1 OT - COP9 OT - CSN OT - FOXO4 OT - SGOC COIS- The authors declare no conflict of interest. EDAT- 2020/10/27 06:00 MHDA- 2020/10/27 06:01 PMCR- 2020/09/23 CRDT- 2020/10/26 05:24 PHST- 2020/02/22 00:00 [received] PHST- 2020/08/19 00:00 [revised] PHST- 2020/10/26 05:24 [entrez] PHST- 2020/10/27 06:00 [pubmed] PHST- 2020/10/27 06:01 [medline] PHST- 2020/09/23 00:00 [pmc-release] AID - ADVS2094 [pii] AID - 10.1002/advs.202000681 [doi] PST - epublish SO - Adv Sci (Weinh). 2020 Sep 23;7(20):2000681. doi: 10.1002/advs.202000681. eCollection 2020 Oct.